Indoles

ABSTRACT

The invention relates to novel 1-(4-(R1R2N-CnH2n-O)phenyl)-5-R42-(4-R3-phenyl)indoles having antifertility and hypocholesterolemic activities and to novel intermediates for their preparation.

Elites States Patent Bell et al. Aug. 5, 1975 INDOLES [75] Inventors:Malcolm R. Bell, East Greenbush; [56] References cued Andrew W. Zalay,Albany, both of Assignee: Sterling Drug Inc., New York, NY.

Filed: Apr. 4, 1973 Appl. No.2 347,620

Related US. Application Data Division of Ser. No. 156,068, June 23,1971, Pat. No. 3,799,943.

US. Cl.260/326.l5; 260/243 B; 260/2475 FP;

260/268 BC; 260/293.61; 260/326.14 R; 260/483; 424/274 Int. Cl. C07D209/14 Field of Search 260/32615, 293.61, 268 BC, 260/243 B, 247.5 FP,326.14 R

OTHER PUBLICATIONS Bell et al., J. Med. Clzenr, (1970) Vol. 664668.

Primary ExaminerDonald G. Daus Assistant E.\'aminerDiana G. RiversAttorney, Agent, or FirmFrederik W. Stonner; B. Woodrow Wyatt 5 7ABSTRACT 11 Claims, N0 Drawings INDOLES This application. is a divisionof copending application Ser. No. l56,068, filed June 23, 1971, now,U.S.Pat. No. 3,799,943. issued Mar. 26, i974.

The invention relates to novel derivatives of L2- diphenylindolcs(formula I below) and to novel intermediates for their preparation.

in one aspect of the invention there are provided novel l-[4-(R,R NC,,H,,O)phenyl]--R ,-2-(4-R,,- phenyl)indoles having the formula where R,and R- which 'can be the same or different, are lower-alkyl, o.r ,R, andR together with the nitrogen form a heterocyciicuring;selected froml-pyrrolidyl, ipiperidyl, l-pipera-z-inyl, .4-lower-alkyl-l-piperazinyl, 4-phenyl-l-pip'erazinyl, 4-morpholinyl and 14- ,thiomorpholinyl ahdwsuchflrings substituted on carbon by from onetothreelower-alkyl.substituents, and n is an integer from-2 to=l 4inclusive; R is hydrogen, lower- I where R is 'hydrogen, lower-alkyl,lower-alkoxy or halo; R, is hydrogen, lower-alkyl, lower-alkoxy orbenzoyloxy; and R is hydrogen or benzyl.

in still another aspect of this invention there are provided thecompounds of the formula where R 'is hydrogen, lower-alkyl, lower-alkoxyor halo;'-R is hydrogen, lower-alkyl, lower-'alkoxy or benzoyloxy;' andR;=, is hydrogen or benzyl. Throughout the specification the term"lower-alkyl and' lower'-al-koxy mean such groups having from one tofour carbon atoms which can be 'straightor branched as ill u st'ra'tec'iby methyl, ethyl, propyl, isopropyl, butyl, isobutyL tertiary-butyl forlower-alkyl" and methoxy, ethoxy, propoxy, isopropoxy, butoxy,is'obutoxy and tertiary-butoxy for lower-alkoxy, the radical C,,Hw'her'e nis an integer from 2 to' 4, represents alkylene, which can bestraight or branched, as illustrated by, but not t0, -CH2CH2,-CH2CH2CH2, CH-(Cl-l )CH -CH(CH )CH(CH3), and -'GH H CH CH and the term.halo means chloro, bromo, fluoro and iodo. 1 Throughout thisspecification where'-.C,,H ,,NR,R comprehendsheretocyclic ringssubstituted on carbon by fromlone-to three lower-alkyl substituents, thelower-alkyllsubstituents can be attached to any available ring carbonatom, and such rings are illustrated by. but not limited to,Z-methyl-l-piperidyl, 4-methyl-lpiperidyl, 3-ethyl-l-piperidyl,2,6-dimethyl-l-piperidyl, 2,4-dimethyll piperidyl, 2,4,6-trimethyll-piperidyl, 3-propyl-l-piperidyl, 2,5-dimethyl-l-pyrrolidyl,2,3-dimethyl-4-morpholinyl, 2-ethyl-4-morpholinyl, 3-ethyl-l-piperazinyland 2,4,6-trimethylpiperazinyl.

T-h'e'i'compounds as illustratedby the compounds of formula I, areuseful both in the free base form and in the form of acid-additionsalts, and both forms are within the purview of the invention. Theacid-ad 'tion salts are simply a more convenient form for use, and inpractice, use of the salt form inherently amounts to use of the baseform. For pharmaceutical purpoaes, the acids which can be used toprepare the acid-addition salts include preferably those which produce,when combined with the free base, medicinally acceptable salts, that is,salts whose anions are relatively innocuous to the animal organism inmedicinal doses of the salts, so that the beneficial properties inherentin the free base are not vitiated by side effects ascribable to theanions. Appropriate medicinally acceptable salts within the scope of theinvention are those derived from mineral acids such as hydrochloricacid, hydrobromic acid, hydriodic acid, nitric acid, phosphoric acid,sulfamic acid, and sulfuric acid; and organic acids such as acetic acid,citric acid, tartaric acid, lactic acid, cyclohexanesulfamic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, quinic acid, and the like, giving thehydrochloride, hydrobromide, hydroiodide, nitrate, phosphate, sulfamate,acetate, citrate, tartrate, lactate, cyclohexanesulfamate,methanesulfonate, ethanesulonate, benzenesulfonate, p-toluenesulfonateand quinate, respectively.

The acid-addition salts of said basic compounds are prepared either bydissolving the free base in aqueous or aqueous-alcohol solutioncontaining the appropriate acid and isolating the salt by evaporatingthe solution. or by reacting the free base and acid in an organicsolvent, in which case the salt separates directly or can be obtained byconcentration of the solution.

Although medicinally acceptable salts of said basic compounds arepreferred for pharmaceutical purposes, all acid-addition salts arewithin the scope of our invention. All acid-addition salts are useful assources of the free base form even if the particular salt per se isdesired only as an intermediate product as for example when the salt isformed only for purposes of purification or identification, or when itis used as an intermediate in preparing a medicinally acceptable salt byion exchange procedures.

The compounds of formula I of this invention possess usefulpharmacological properties as determined by standard test proceduresdescribed hereinbelow. Thus they possess useful antifertility andhypocholesterolemic activities. The actual determination of thenumerical biological data definitive for a particular compound, for eachtype of activity, is readily determined by standard test procedures bytechnicians having ordinary skill in pharmacological test procedures,without the need for any extensive experimentation.

The compounds can be prepared for use by dissolving under sterileconditions salt forms of the compounds in water (or an equivalent amountof a nontoxic acid if the free base is used), or in a physiologicallycompatible aqueous medium such as saline, and stored in ampoules forintramuscular injection. Alternatively, they can be incorporated in unitdosage form as tablets or capsules for oral administration either aloneor in combination with suitable adjuvants such as calcium carbonate,starch, lactose, talc, magnesium t pyrrolidine Q Kl""* Q VII stearate,gum acacia, and the like. Still further the compounds can be formulatedfor oral administration in aqueous alcohol, propylene glycol, or oilsolutions or oil-water emulsions in the same manner as conventionalmedicinal substances are prepared.

The novel compounds of formulas II and Ill above are useful asintermediates for the preparation of the novel compounds of formula I.

The compounds of formula I (R 9* OH) are prepared by reacting analkali-metal salt of an appropriate l-(4-hydroxyphenyl)indole (ll, R =H)with an appropriate amino-lower-alkyl halide of the formula YC,,H ,,NR R(IX), where Y is chloro, bromo or iodo. ln this reaction, the indole ll(R =H) cannot bear a S-hydroxyl substituent (R', OH) since thatsubstituent would also be subject to alkylation with theamino-lower-alkyl halide. The compounds of formula I where R, is hydroxyare prepared by ester hydrolysis of the corresponding compounds where R,is benzoyloxy. The l-(4-hydroxyphenyl)indole (ll, R =H) is obtained byreacting an appropriate cyclohexanone with pyrrolidine, treating the soobtained cyclohexenylamine with an appropriate 2-bromoacetophenone,reacting the resulting oxocyclohexylacetophenone with 4-hydroxy or4-benzyloxyaniline and dehydrogenating the resulting4,5.6,7-tetrahydroindole (III) to give the indole ll (R =H or benzyl).The reaction of the oxocyclohexylacetophenone with 4-benzyloxyanilineand dehydrogenation of the corresponding tetrahydroindole (lll,R;,=benzyl) are preferred for preparing the indole ll where R, isbenzoyloxy, the benzyl substituent serving as a protective group toprevent undesirable side reactions with the benzoyloxy ester duringthese reactions. The l-(4-benzyloxyphenyl)indole ll (R =benzyl) can beconverted to the corresponding indole (ll, R =H) by reductive cleavageof the benzyl ether.

The foregoing reaction steps are illustrated by the following equation:

BrCH C0 R RI 11 -0 NH2 1; 5 VIII g I g II (R5=H) I (R includes OH) Inthe above illustrated reaction steps, R R R R R,, R n and Y have themeanings defined hereinbefore, except where otherwise indicated.

Step (a) is accomplished by heating the cyclohexanone IV with excesspyrrolidine in a suitable solvent. The reaction is conveniently carriedout in benzene at reflux temperature with azeotropic removal of thewater formed until the stoicheometric amount of water has beencollected. The cyclohexanones IV belong to a class of known compoundsand are readily prepared from the corresponding cyclohexanols by astandard oxidative procedure i.e., reaction wth sodium dichromate inwater in the presence of sulfuric acid. The cyclohexanols in turn areprepared from the corresponding known phenols by a standardhydrogenation procedure i.e., subjecting the phenol in ethyl alcohol toa hydrogen atmosphere at about I500 pound per square inch gauge and atabout 90lO0C. in the presence of alkali-free Raney nickel. Step (b) isaccomplished by reacting the cyclohexenylamine V with an equivalent ofthe 2-bromoacetophenone VI in a suitable solvent at elevatedtemperature. The reaction is conveniently carried out in toluene atreflux temperature for about one to three hours. The2-bromoacetophenones (VI) belong to a class of well-known compounds andare readily prepared from the known corresponding acetophenones bystandard bromination procedures. A convenient procedure involves addingbromine in chloroform dropwise to a solution of the appropriateacetophenone in chloroform at about 2C. and stirring the resultingsolution for about 3 to 4 hours. The resulting 2-bromoacetophenone canbe isolated and purified using standard procedures. Step (c) isaccomplished by reacting the oxocyclohexylacetophenone VII with anequivalent of the aniline VIII in glacial acetic acid. The reaction isconveniently carried out at reflux temperature for about one-half hour.The anilines VIII are known compounds. Step ((1) is carried out byheating the 4,5,6,7-tetrahydroindole III in a suitable solvent in thepresence of palladium-on-charcoal at an appropriate temperature adequateto affect aromatization. The reaction is conveniently carried out inmesitylene at reflux temperature in a nitrogen atmosphere in thepresence of percent palladium-on-charcoal for from 3 hours to 3 days.Step (e) is accomplished by subjecting the indole II (R =benzyl) inethyl alcohol to a hydrogen atmosphere at about 50 to 60 pounds persquare inch gauge over 10 percent palladium-on-charcoal catalyst at roomtemperature until the stoichiometric amount of paring an alkali-metalsalt of the indole II (R,-,=I-I)'in a suitable solvent, adding theamino-Iower-alkyl halide IX, in a suitable solvent if desired. andheating the reaction mixture. The reaction is conveniently carried outby reacting a solution of the indole II (R,-,=H) in chlorobenzene with aslight excess of sodium methoxide at reflux temperature withdistillation of part of the solvent, cooling the mixture containing thesodium salt of the indole, adding an amount, equivalent to the amountofsodium methoxide used, of the amino-lower-alkyl halide, neat or as asolution in benzene or chlorobenzene, and heating under reflux for about4 hours. The aminolower-alkyl halides (IX) are commercially availablecompounds or can be prepared-by standard preparative methods. Step (g)is carried out by dissolving the indole I (R.,=benzoyloxy) in aqueousethyl alcohol containing an excess of sodium hydroxide and refluxing forabout one-half to 1 hour and isolating the product by standardprocedures.

The compounds of formula, I where R. is loweralkoxy can also be preparedby reacting the alkalimetal salt of the corresponding indole (I, R =OH)with an appropriate lower-alkyl halide i.e., chloride, bromide oriodide, using a procedure similar to that described above for step (f).The lower-alkyll'ialidesare commercially available compounds or arereadilyprepared by standard preparative methods.

TEST PROCEDURE FOR THE DETERMINATION OF ANTIFERTILITY ACTIVITY Maturefemale rats were medicated daily 'with the test agent for'6 days afterinsemination by proven male rats (a total of six medications). The ratswere autopsied 15 days after insemination and their uteri were removedand examined for evidence of pregnancy. The

test agents were administered either as suspensions, de

in .10 percent of the free base) according to the procedure describedabove. Thus, they are indicated for use as antifertility agents.

TEST PROCEDURE FOR THE DETERMINATION OF HYPOCHOLESTEROLEMIC ACTIVITYMale rats were fasted for hours, medicated with the test agent in gumtragacanth via stomach tube and then fed. This regimen was continuedfour days. A control group of male rats was subjected to the sameregimen except that they were not medicated with the test agent. On thefifth day, blood was taken by cardiac puncture and serum samples wereanalyzed for cholesterol. The test agents were considered to havehypocholesterolemic activity if there was a significant decreasepercent) in the serum cholesterol level of the medicated rats from thatof the control rats.

The compounds of formula 1 were found to effectivcly decrease serumcholesterol levels by from 43 to 80 percent when administered by gavageto male rats at a dose of 256 mg/kg X 4 days according to the above testprocedure. Thus, they are indicated for use as hypocholesterolemicagents, that is, as agents for lowering blood cholesterol levels.

The molecular structures of the compounds of this invention wereassigned on the basis of the method of their synthesis and study oftheir infrared spectra, and confirmed by the correspondence betweencalculated and found values for the elementary analysis forrepresentative examples.

The following examples will further illustrate the invention:

EXAMPLE 1 1 {4-[Z-(Diethylamino)ethoxy1phenyl }-5-methoxy-2-phenylindole A. N-(4-Methoxy-1-cyclohexenyl)pyrrolidine A solution of85.4 g. of 4-methoxycyclohexanone and 83.3 ml. of pyrrolidine in 500 ml.of benzene was heated under reflux for four hours during which time thewater formed was separated by means of a water trap. The mixture wasconcentrated, toluene was added, and the mixture was distilled until nopyrrolidine was detected in the distillate. This solution of crudeN-(4-methoxy-1-cyclohexenyl)pyrrolidine was used in step 3. B.2-(5-Methoxy-2-oxocyc1ohexyl)acetophenone A solution ofN-(4-methoxy-l-cyclohexenyl)pyrrolidine (0.65 mole) and 130 g. of2-bromoacetophenone in 600 ml. of toluene was heated under reflux withstirring for 3 hours and cooled. The crude hydrobromide salt of thepyrrolidine enamine of 2-(2-oxocyclohexyl- )acetophenone was filtered,dissolved in 250 ml. of water and the solution was warmed on asteambath. The resulting brown oily layer was extracted into chloroform,dried, and the extract was concentrated under reduced pressure to give130 g. of a brown oil, distil1ation of 98.8 g. .of which yielded 57.6 g.of 2-(5- methoxy-2-oxocyc1ohexyl)acetophenone; b.p. l71177C. (0.05-0.06mm). C. 1-(4-Hydroxyphenyl)-5-methoxy-2-phenyl-4,5,6,7- tetrahydroindoleA solution of 24.63 g. of 2-(5-methoxy-2-oxocyclohexyl)acetophenone and10.9 g. of 4-aminophenol in 60 ml. of glacial acetic acid was heatedunder reflux for one-half hour, diluted with 30 ml. of water and cooled.The crystals were filtered, washed with water and recrystallized frommethyl alcohol to give 27.4 g.

of 1-(4-hydroxyphenyl)-5-methoxy-2-phenyl-4,5.6,7- tetrahydroindole'.m.p. 1.74-175C. D. 1-(4-Hydroxyphenyl)-5-methoxy-2-phenylindo1e To asolution of 27.4 g. of 1-(4-hydroxyphenyl)-5-methoxy-2-phenyl-4,5,6,7-tetrahydroindole in 500 ml. of mesitylene wasadded 20 g. of 10 percent palladiumon-charcoal and the mixture washeated under reflux in a nitrogen atomosphere for three days, filteredhot and concentrated. The resulting crystals were filtered andrecrystallized first from chloroform-carbontetrachloride and then fromisopropyl alcohol to give 14.1 g. ofl-(4-hydroxypheny1)-5-methoxy-2-pheny1indo1e; m.p. 200-201C. E.1-{4-[2-(Diethylamino)ethoxy]phenyl}-5-methoxy- Z-phenylindole A stirredmixture of 10.6 g. of l-(4-hydroxypheny1)- 5-methoxy-2-pheny1indole in150 ml. of chlorobenzene and 2.2 g. of sodium methoxide in 10 ml. ofmethyl alcohol was distilled until 20 ml. of distillate had beencollected, cooled, and 16 ml. of a 2.5-N solution ofN-(2-ch1oroethyl)diethylamine in toluene was added and the mixture washeated under reflux with stirring for four hours and 5 ml. of 35 percentsodium hydroxide and 80 ml. of water was added to the warm mixture andstirring was continued for one-half hour. The layers were separated, theaqueous layer was extracted with ether and the combined organicsolutions were dried and concentrated to dryness under reduced pressureto give 14 g. of crude product. To a warm solution of 13 g. of thiscrude base in 30 ml. isopropyl alcohol was added a solution ofp-toluenesulfonic acid monohydrate in 18 ml. of isopropyl alcohol and100 ml. ether was slowly added. The resulting crystals were filtered togive, after recrystallization from isopropyl alcoholether, 8.1 g. of1-{4-[2-(diethylamino)ethoxy]pheny1}- 5-methoxy-2-phenylindolep-toluenesulfonate; m.p. 131l32C.

Preparation of 4-Methoxycyc1ohexanone intermediate for Example 1A Asolution of 496.52 g. (4 mole) of 4-methoxypheno1 in 400 ml. absoluteethyl alcohol was subjected to a hydrogen atmosphere in the presence of60 g. alkali-free Raney nickel at 1800 p.s.i.g. and about 90C. When theuptake of hydrogen was completed (about 2 hours) the mixture wasfiltered, concentrated and the residue was distilled to give 360 g. ofliquid; b.p. 101110C. (1 1-12 mm); redistillation of 230 g. of thisliquid yielded 160.1 g. of 4-methoxycyc1ohexano1; b.p. 96100C. (8.5 mm);m, 1.4681. 4- Methoxycyclohexanol (130.18 g.; 1 mole) was added to astirred solution of 20 g. of sodium dichromate dihydrate (0.69 mole) insulfuric acid (prepared by adding 93.5 ml. of concentrated sulfuric acidto 1 liter of water) at 0C. The reaction temperature rose to 20C.,slight warming was applied and the temperature rose to C. and stirringwas continued for 1 hour. The mixture was cooled, extracted withmethylene dichloride and ether and the extracts were dried andconcentrated to give 90 g. ofliquid, distillation of which gave 48.8 g.of 4-methoxycyc1ohexanone; b.p. 82C. (7.5 mm).

The 4-R' -cyclohexanones (1V), intermediates for the preparation of thecompounds of the invention, can be prepared using the above-describedprocedures, but substituting for 4-methoxyphenol an equivalent amount ofappropriately-4-substituted phenols.

EXA M PLE 2 l -{4-12-(Diethylamino)ethoxy]pheny1}-2- phe'nylindole A.N-( l-Cyclohexenyl)pyrrolidine Following a procedure similar to that ofExample l(A) but using 392 g. of cyclohexanone and 533 ml. ofpyrrolidine in 800 ml. benzene there was obtained. on evaporation todryness of the reaction solution and distillation of the residue, 495 g.of N-( l-cyclohexenyl)- pyrrolidine; b.p. 70-72C. (0.5-1 mm). B.2-(2-Oxocyclohexyl)acetophenone Following a procedure similar to that ofExample l(B) but using 403 g. of N-( l-cyclohexenyl)pyrrolidine and 530g. of Z-bromoacetophenone in 1 liter of toluene there was obtained 245g. of 2-(2-oxocyclohexyl- )acetophenone; b.p. l60-167C. (0.8-1.7 mm). C.-l-(4-Hydroxyphenyl)-2-phenyl-4.5v,6.7-

tetrahydroindol A Following a procedure similar to that of Example l(C)but using 216.3 g. of 2-(2-oxocyclohexyl- )acetophenone and,l09.l.-g. of4-aminophenol in 650 ml. glacial acetic acidlthere was obtained 227 g.of .l- (4-hydroxyphenyl)-2-phenyl-4,5,6,7-tetrahydroindole; m.p.18ll82C. (isopropyl alcohol). D. l-(4-Methoxyphenyl)-2-phenyl-4,5.6.7-

tetrahydroindole Following a procedure similar to that of Example l(C)but using 64 .9; .g. of 2-(2-oxocyclohexyl- )acetophenone and 37 g. of4-methoxyaniline in 180 ml. glacial acetic acid there was obtained 80.9g. of 1- (4-methoxyphenyl)-2-phenyl-4,5,6,7-tetrahydroindole; m.p.l32-l33C. (isopropyl alcohol). E. l-(4-Methoxyphenyl)-2-phenylindoleFollowing a procedure-similar to that of Example l(D) but using 63 g.-ofI-(4-methoxyphenyl)-2-phenyl- 4,5,6.7-tetrahydroindole and 18 g. ofpercent palladium-on-charcoal in 600 ml. mesitylene (18 hours reflux)there was 1 obtained, on recrystallization first from isopropyl alcoholand then from tetrahydrofuram hexane, 58.5 g. of l-(4-methoxyphenyl)-2-phenylindole; mip. l41-"-'142C. F. l-(4-Hydroxyphenyl)-2-phenylindoleFollowing a procedure similar to that of Example l(D) but' using 202 g.of l-(4-hydroxyphenyl)-2- phenyl-4,5,6,7 tetrahydroindole and 35 g. of10 percent palladium-on-charcoal in 1900 ml. of mesitylene (6 hoursreflux) there was obtained, on recrystallization from benzene-cyclohexane, 157 g. of l-(4- 5O g. of N-(2-chloroethyl)diethylaminethere was obtained 35 g. of crude product, 32 g. of which was convertedto 30.1 g. of l-{4-[Z-(diethylamino)ethoxylphenyl} -2-phenylindole l23-l24C. (isopropyl alcohol). A solution of the free base'in chloroform wasshaken with a slight excess of concentrated hydrochloric acid in water.the layers were separated. dried and concentrated. The residue wasdissolved in isopropyl alcohol. concentrated. and diluted with ethylacetate. The resulting solids were filtered to give 1-{4-[Z-(diethylamino)ethoxy]phenyl}-2- phenylind'ole hydrochloride; m.p.l54-l55C.

EXAMPLE 3 l-{4-[2-( l-Pyrrolidyl)ethoxy]phenyl}2-phenylindole EXAMPLE 4A. N-(4-Benz oyloxy-l-cyc1ohexenyl)pyrrolidine Following a proceduresimilar to that of Example l(A) but using 21.82 g. of4-benzyloxycyclohexanone and 12.5 ml. of pyrrolidine in 200 ml.ofbenzene there was obtained a toluene solution of crude N-(4-benzoyloxy-1-cyclohexenyl)pyrrolidine which was used in the next step.

B. 2-(5-Benzoyloxy-2-oxocyclohexyl)acetophenone Following a proceduresimilar to that described in Example 2(A) but usingN-(4-benzoyloxy-l-cyclohexyl)pyrrolidine (0.1 mole) and 20 g. of t 2-bromoacetophenone in ml. of toluene there was obtained 25.4 g. of2-(5-benzoyloxy-2-oxocyclohexyl- )acetophenone; m.p. lO7lO8C. (methylalcohol).

C. l-(4 Benzyloxyphenyl)-5-benzoyloxy-2-phenyl- 4.5.6.7-tetrahydroindoleFollowing a procedure similar to that described for Example l(C) butusing 13.5 g. of 2-(5-benZoyloxy-2- oxocyclohexyl)acetophenone and 8 g.of 4- benzyloxyaniline in 40 ml. of glacial acetic acid there wasobtained, after recrystallization from isopropyl alcohol andbenzene-cyclohexane. 16.2 g. of l-(4-benzyloxyphenyl)-5-benzoyloxy-2-phenyl-4,5.6.7- tetrahydroindole; m.p.l24l25C.

Following a procedure similar to that described in Example l(D) butsubstituting for l-(b 4- hydroxyphenyl)-5-methoxy-2-phenyl-4,5,6,7-tetrahydroindole an equivalent amount of l-(4-benzyloxyphenyl)-5-benzoyloxy-2-phenyl-4,5,6,7- tetrahydroindole therecan be obtained benzyloxyphenyl)-5-benzoyloxy-Z-phenylindole.

By subjecting 1-(4-benzyloxyphenyl)-5-benzoyloxy- Z-phenylindole to thestandard debenzylation procedure described hereinbefore there can beobtained 1- (4-hydroxyphenyl)-5-benzoyloxy-Z-phenylindole.

Following a procedure similar to that described in p-toluenesulfonate;m.p.'

1 1 Example l(E) but substituting for l-(4-hydroxyphenyl)--methoxy-2-phenylindole an equivalent amount ofl-(4-hydroxyphenyl)-5-benzoyloxy-2- phenylindole there can be obtainedl-{4-l2- (diethylamino)ethoxylphenyl}5-benzoyloxy-2- phenylindole,

By subjecting I l-{4-[2- (diethylamino)ethoxy]phenyl}-5-benzoyloxy-2phenylindole to the standard ester hydrolysis procedure describedhereinbefore there can be obtained]-{4-lZ-(diethylamino)ethoxy]phenyl}-5-hydroxy-2- phenylindole.

Following a procedure similar to that of Example l(E) but substitutingfor -(2-chloroethyl)diethy|amine an equivalent amount ofN-(Z-chloroethyl)diisopropylamine,

N-(2-chloroethyl)morpholine,

N-(2-chloroethyl)thiomorpholine,

N-(Z-ehloroethyl)piperidine.

N-(2-chloroethyl)piperazine,

N-( 2-chloroethyl )-N -methylpiperazine,

N-(2-chloroethyl) N-phenylpiperazine.

N-( 2-chloro-l ,Z-dimethylethyl )dimethylan'iine,

N-(2-chloropropyl)-N-ethyl-N-methylamine, and

N-(4-chlorobutyl)dimethylamine there can be obtained, respectively.

I-{ 4-[ 2-( diisopropylamino )ethoxy]phenyl}-S- methoxy-Z-phenylindole,l-{4-l2-(4-morpholinyl)ethoxy]phenyl}-5-methoxy- Z-phenylindole,l-{4[2-(4-thiomorpholinyl)ethoxy]phenyl}-5- methoxy-2-phenylindole,

l-{4-[ 2-( l-piperidyl )ethoxy]phenyl}-5-methoxy-2- phenylindole,

l-{4-[2-( l-piperazinyl)ethoxy]phenyl}-5-methoxy- Z-phenylindole,

l-{4-[2-(4-methyl-l-piperazinyl)ethoxy]phenyl}-5-methoxy-2-phenylindole,

l-{4-[2-(4phenyl-1-piperazinyl)ethoxylphenyl}-5 methoxy-Z-phenylindole,

l-{4-[2-(dimethylamino)-l,2-

dimethylethoxy]phenyl}-5-methoxy-2- phenylindole,

l- {4-[ 2-( N-ethyl-N-methylamino lmethylethoxy1phenyl}-S-methoxy-Z-phenylindole, and

l-{4-[4-(dimethylamino)butoxy]phenyl}-5- methoxy-Z-phenylindole.

Following a procedure similar to that of Example l(A) but substitutingfor 4-methoxycyclohexanone an equivalent amount of4-methylcyclohexanone,

4-isopropylcyclohexanone,

4-butylcyclohexanone,

4-propoxycyclohexanone, and

4-tert-butoxycyclohexanone there can be obtained, respectively,

N-(4-methyl-l-cyclohexenyl)pyrrolidine,

N-(4-isopropyl-l-cyclohexenyl)pyrrolidine,

N-(4-butyll -cyclohexenyl )pyrrolidine,

N-(4-propoxy-l-cyelohexenyl)pyrrolidine, and

N-(4-tert-butoxy-l-cyclohexenyl)pyrrolidine.

Following a procedure similar to that of Example l(B) but substitutingfor N-(4-methoxy-l-cyclohexenyl)pyrrolidine an eqivalent amount of thepyrrolidines listed in the previous paragraph, and for 2-bromoacetophenone respectively amount of the following,

4-chloro-2bromoacetophenone, 4-methoxy-Z-bromoacetophenone.4'-butyl-2-bromoacetophenone. 4-fluoro-2-bromoacetophenone, and4-methyl-2-bromoacetophenone, there can be obtained, respectively,2-(S-methyl-Z-oxocyelohexyl)-4'- chloroacetophenone,2-(5-isopropyl-2-oxocyclohexyl)-4'- mcthoxyacetophenone,2-(5-butyl-2-oxocyclohexyl)-4'-butylacetophenone,2-(5-propoxy-2-oxocyclohexyl)-4'- fluoroacetophenone, and2-(5-tert-butoxy-Z-oxocyclohexyl)-' 4'methylacetophenone. Theabove-named 2-bromoacetophenones can be prepared from the correspondingknown acetophenones following the general procedure describedhereinbefore.

Following a procedure similar to that of Example l(B) but substitutingfor Z-bromoacetophenone an equivalent amount of2-bromo-4-bromoacetophen'one.

2-bromo-4-tert-butox'yacetophenone, 2-bromo-4-ethoxyaeetophenone. and2-bromo-4'-isopropylacetophenone there can be obtained, respectively,

2-(S-methoxy-Z-oxocyclohexyl)-4"- bromoacetophenone,2-(5-methoxy-2-oxocyclohexyl)-4'-tertbutoxyaeetophenone 2-(5-methoxy-2oxocyelohexyl)-4'- ethoxyacetophenone, and2-(5-methoxy-2-oxocyclohexyl)-4'- isopropylacetophenone. 1 Theabove-named Z-bromoacetophenones can be prepared from the correspondingknown aeetophenones following the general procedure describedhereinbefore.

Following a procedure similar to that of Example l(C) but substitutingfor 2-(5-methoxy-2oxocyclohexyl)acetophenone an equivalent; amount ofthe cyclohexylacetophenoneslisted in theprevious two paragraphs therecan be obtained, respectively,

l-( 4-hydroxyphenyl )-5-methyl-2-( 4-chlorophenyl4,5,6,7-tetrahydroindole, l-(4-hydroxyphenyl)-5-isopropyl-2-(4-methoxyphenyl)-4,5,J-tetrahydroindole, l-(4-hydroxyphenyl)-5-butyl-2-(4-butylphenyl)- 4,5,6,7-tetrahydroindole,l-(4-hydroxyphenyl)-5-propoxy-2-(4-fluorophenyl)- 4,5,6,7tetrahydroindole, l-(4-hydroxyphenyl)-5-tert-butoxy-2 (4-methylphenyl)-4,5,6,7-tetrahydroindole,l-(4-hydroxy'phenyl)-5methoxy-2-(4-bromophenyl)-4,5,6,7-tetrahydroindole,l-(4-hydroxyphenyl)-5-methoxy-2-(4-tertbutoxyphenyl)-4,5,6,7-tetrahydroindole,l-(4-hydroxyphenyl)-5-methoxy-2-(4- ethoxyphenyl)-4,5,6,7-tetrahydroindole, and l=(4-hydroxyphenyl)-5-methoxy-2-(4-isopropylphenyl)-4,5,6.7-tetrahydroindole.

Following a procedure similar to that of Example l(D) but substitutingfor l-(4-hydroxyphenyl)-5- an equivalentmethoxy-2-phenyl-4.5,6,7-tetrahydroindole an equivalent amount of thetetrahydroindoles listed in the previous paragraph there can beobtained. respectively,

l-(4-hydroxyphenyl)-5-methyl-2-(4- chlorophenylfindole,l-(4-hydroxyphenyl)-5-isopropyl-2-(4-methoxyphenyl)indole,l-(4hydroxyphenyl)5-butyl-2-(4 butylphenyl)indole,l-(4-hydroxyphenyl)-5-propoxy2-(4- fluorophenyUindole,l-(4-hydroxyphenyl)-5-tert-butoxy2-(4- methylphenyl)indole,l-(4-hydroxyphenyl)-5-methoxy-2-(4- bromophenyl)indole, l-(4-hydroxyphenyl )--methoxy-2-( 4-tert-butoxyphenyl)indole,l-(4-hydroxyphenyl)-5-methoxy-2-(4-ethoxyphenyl- )indole, andl-(4-hydroxyphenyl)-5-rnethoxy-2-(4-isopropylphenyl)indole.

Following a procedure similar to that of Example 1(E) but substitutingfor l-(4-hydroxyphenyl)-5- methoxy-phenylindole an equivalent amount ofthe indoles listed in the previous paragraph there can be obtained,respectively,

(4-chlorophenyl)indole,l-{4-[Z-(diethylamino)ethoxy]phenyl}-5-isopropyl-2-(4-methoxyphenyl)indole,l-{4-[2-(diethylamino)ethoxy]phenyl}-5-butyl-2-(4- butylphenyl)indole,l-{4-[2-(diethylamino)ethoxy]phenyl}-5-propoxy-2-(4-fluorophenyl)indole,

l- {4-[ 2-(diethylamino )ethoxy]phenyl}5-tertbutoxy-2-(4-methylphenyl)indole,

2-(4-bromophenyl)indole, 1-{4-[2-(diethylamino)ethoxylphenyl}-5-methoxy-2-(4-tertbutoxyphenyl)indole,

l-{4-[ 2-(diethylamino)ethoxy]phenyl}-5-methoxy-2-(4-ethoxyphenyl)indole, andl-{4-[2-(diethylamino)ethoxy]phenyl}-5-methoxy-2-(4isopropylphenyl)indole.

We claim:

1. A compound of the formula 14 where R, and R are lower-alkyl, or R,and R together with the nitrogen form a heterocyclic ring selected fromlpyrrolidyl, l-piperidyl, l-piperazinyl. 4-loweralkyl-l-piperazinyl.4-phenyl-l-piperazinyl, 4- morpholinyl, 4-thiomorpholinyl and such ringssubstituted on carbon by one to three lower-alkyl substituents, and n isan integer from 2 to 4 inclusive:

R is hydrogen, lower-alkyl, lower-alkoxy or halo;

and

R is hydrogen. lower-alkyl, lower-alkoxy. benzoyloxy and hydroxy.

2. A compound of the formula 6. l-{4-[2-(Diethylamino)ethoxy]phenyl}-2-methoxy-2-phenylindole according to claim 5.

7. l-{4-[2-(Diethylamino)ethoxy]phenyl}-2- phenylindole according toclaim 5.

8. A compound according to claim 2 where R and R together with thenitrogen form l-pyrrolidyl.

9. A compound according to claim 8 where R,, is hydrogen or lower-alkyl.

10. A compound according to claim 9 where n is the integer 2.

ll. l-{4-[2-(Pyrrolidyl)eth0xy]phenyl}-2- phenylindole according toclaim 10.

1. A COMPOUND OF THE FORMULA
 2. A compound of the formula
 3. A compoundaccording to claim 2 where R1 and R2 are lower-alkyl.
 4. A compoundaccording to claim 3 where R4 is hydrogen, lower-alkyl or lower-alkoxy.5. A compound according to claim 4 where n is the integer
 2. 6.1-(4-(2-(Diethylamino)ethoxy)phenyl)-2-methoxy-2-phenylindole accordingto claim
 5. 7. 1-(4-(2-(Diethylamino)ethoxy)phenyl)-2-phenylindoleaccording to claim
 5. 8. A compound according to claim 2 where R1 and R2together with the nitrogen form 1-pyrrolidyl.
 9. A compound according toclaim 8 where R4 is hydrogen or lower-alkyl.
 10. A compound according toclaim 9 where n is the integer
 2. 11.1-(4-(2-(Pyrrolidyl)ethoxy)phenyl)-2-phenylindole according to claim 10.